Prediction and causal reasoning in planning

Nonlinear planners are often touted as having an efficiency advantage over linear planners. The reason usually given is that nonlinear planners, unlike their linear counterparts, are not forced to make arbitrary commitments to the order in which actions are to be performed. This ability to delay commitment enables nonlinear planners to solve certain problems with far less effort than would be required of linear planners. Here, it is argued that this advantage is bought with a significant reduction in the ability of a nonlinear planner to accurately predict the consequences of actions. Unfortunately, the general problem of predicting the consequences of a partially ordered set of actions is intractable. In gaining the predictive power of linear planners, nonlinear planners sacrifice their efficiency advantage. There are, however, other advantages to nonlinear planning (e.g., the ability to reason about partial orders and incomplete information) that make it well worth the effort needed to extend nonlinear methods. A framework is supplied for causal inference that supports reasoning about partially ordered events and actions whose effects depend upon the context in which they are executed. As an alternative to a complete but potentially exponential-time algorithm, researchers provide a provably sound polynomial-time algorithm for predicting the consequences of partially ordered events

Asking the experts : developing and validating parental diaries to assess children's minor injuries

The methodological issues involved in parental reporting of events in children's everyday lives are discussed with reference to the development and validation of an incident diary, collecting concurrent data on minor injuries in a community study of children under eight years old. Eighty-two mothers participated in a comparison over nine days of daily telephone interviews and structured incident diaries. Telephone methods resulted in more missing data, and participants in both groups expressed a preference for the diary method. This diary was then validated on a sample of 56 preschool and school-aged children by comparing injury recording by a research health visitor with that of their mothers. Each failed to report some injuries, but there was good agreement overall, and in descriptive data on injuries reported by both. Parental diaries have the potential to provide rich data, of acceptable validity, on minor events in everyday life

Factors influencing the implementation of fall-prevention programmes: a systematic review and synthesis of qualitative studies

BACKGROUND: More than a third of people over the age of 65 years fall each year. Falling can lead to a reduction in quality of life, mortality, and a risk of prolonged hospitalisation. Reducing and preventing falls has become an international health priority. To help understand why research evidence has often not been translated into changes in clinical practice, we undertook a systematic review and synthesis of qualitative research in order to identify what factors serve as barriers and facilitators to the successful implementation of fall-prevention programmes. METHODS: We conducted a review of literature published between 1980 and January 2012 for qualitative research studies that examined barriers and facilitators to the effective implementation of fall-prevention interventions among community-dwelling older people and healthcare professionals. Two reviewers independently screened studies for inclusion, extracted data, and assessed methodological quality according to predefined criteria. Findings were synthesised using meta-ethnography. RESULTS: Of the 5010 articles identified through database searching, 19 were included in the review. Analysis of the 19 studies revealed limited information about the mechanisms by which barriers to implementation of fall-prevention interventions had been overcome. Data synthesis produced three overarching concepts: (1) practical considerations, (2) adapting for community, and (3) psychosocial. A line of argument synthesis describes the barriers and facilitators to the successful implementation of fall-prevention programmes. These concepts show that the implementation of fall-prevention programmes is complex and multifactorial. This is the first systematic review and synthesis of qualitative studies to examine factors influencing the implementation of fall-prevention programmes from the perspectives of both the healthcare professional and the community-dwelling older person. CONCLUSIONS: The current literature on barriers and facilitators to the implementation of fall-prevention programmes examines a variety of interventions. However, the ways in which the interventions are reported suggests there are substantial methodological challenges that often inhibit implementation into practice. We recommend that successful implementation requires individuals, professionals, and organisations to modify established behaviours, thoughts, and practice. The issues identified through this synthesis need to be fully considered and addressed if fall-prevention programmes are to be successfully implemented into clinical practice.National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West of EnglandEuropean Regional Development FundEuropean Social Fund Convergence Programme for Cornwall and the Isles of Scill

Saturable metabolism of continuous high-dose ifosfamide with Mesna and GM-CSF: A pharmacokinetic study in advanced sarcoma patients

Background: The aim of this study was to assess the pharmacology, toxicity and activity of high-dose ifosfamide/mesna ± GM-CSF administered by a five-day continuous infusion at a total ifosfamide dose of 12-18 g/m2 in adult patients with advanced sarcomas. Patients and methods: Between January 1991 and October 1992 32 patients with advanced or metastatic sarcoma were entered the study. Twenty-seven patients were pretreated including twenty-three with prior ifosfamide at less than 8 g/m2 total dose/cycle. In 25 patients (27 cycles) extensive pharmacokinetic analyses were performed. Results: The area under the plasma concentration-time curve (AUC) for ifosfamide increased linearly with dose while the AUC's of the metabolites measured in plasma by thin-layer chromatography did not increase with dose, particularly that of the active metabolite isophosphoramide mustard. Furthermore the AUC of the inactive carboxymetabolite did not increase with dose. Interpatient variability of pharmacokinetic parameters was high. Dose-limiting toxicity was myelosup-pression at 18 g/m2 total dose with grade 4 neutropenia in five of six patients and grade 4 thrombocytopenia in four of six patients. Therefore the maximum tolerated dose was considered to be 18 g/m2 total dose. There was one CR and eleven PR in twenty-nine evaluable patients (overall response rate 41%). Conclusion: Both the activation and inactivation pathways of ifosfamide are non-linear and saturable at high-doses although the pharmacokinetics of the parent drug itself are dose linear. Ifosfamide doses greater than 14-16 g/m2 per cycle appear to result in a relative decrease of the active metabolite isophosphoramide mustard. These data suggest a dose-dependent saturation or even inhibition of ifosfamide metabolism by increasing high dose ifosfamide and suggest the need for further metabolic studie

Pharmacokinetics and metabolism of ifosfamide in relation to DNA damage assessed by the COMET assay in children with cancer

The degree of damage to DNA following ifosfamide (IFO) treatment may be linked to the therapeutic efficacy. The pharmacokinetics and metabolism of IFO were studied in 19 paediatric patients, mostly with rhabdomyosarcoma or Ewings sarcoma. Ifosfamide was dosed either as a continuous infusion or as fractionated doses over 2 or 3 days. Samples of peripheral blood lymphocytes were obtained during and up to 96 h after treatment, and again prior to the next cycle of chemotherapy. DNA damage was measured using the alkaline COMET assay, and quantified as the percentage of highly damaged cells per sample. Samples were also taken for the determination of IFO and metabolites. Pharmacokinetics and metabolism of IFO were comparable with previous studies. Elevations in DNA damage could be determined in all patients after IFO administration. The degree of damage increased to a peak at 72 h, but had returned to pretreatment values prior to the next dose of chemotherapy. There was a good correlation between area under the curve of IFO and the cumulative percentage of cells with DNA damage (r2 = 0.554, P = 0.004), but only in those patients receiving fractionated dosing. The latter patients had more DNA damage (mean ± s.d., 2736 ± 597) than those patients in whom IFO was administered by continuous infusion (1453 ± 730). The COMET assay can be used to quantify DNA damage following IFO therapy. Fractionated dosing causes a greater degree of DNA damage, which may suggest a greater degree of efficacy, with a good correlation between pharmacokinetic and pharmacodynamic data

The Birmingham Boron Neutron Capture Therapy (BNCT) project : developments towards selective internal particle therapy

This paper will review progress on two aspects of the Birmingham BNCT project. Firstly on evaluation of the effects of high and low LET radiations when delivered simultaneously, and secondly on attempts to optimise delivery of the boron carrier compound BPA through pharmacokinetic studies. Simultaneous or non-simultaneous irradiations of V79 cells with alpha-particle and X-ray irradiations were performed. Alpha doses of 2 and 2.5 Gy were chosen and the impact on survival when delivered separately or simultaneously with variable doses of X-rays was evaluated. The pharmacokinetics of the delivery of a new formulation of BPA (BPA-mannitol) are being investigated in brain tumour patients through a study with 2 × 2 design featuring intravenous and intracarotid artery infusion of BPA, with or without a mannitol bolus. On the combined effect of low and high LET radiations, a synergistic effect was observed when alpha and X-ray doses are delivered simultaneously. The effect is only present at the 2.5 Gy alpha dose and is a very substantial effect on both the shape of the survival curve and the level of cell killing. This indicates that the alpha component may have the effect of inhibiting the repair of damage from the low LET radiation dose delivered simultaneously. On the pharmacokinetics of BPA, data on the first three cohorts indicate that bioavailability of BPA in brain ECF is increased substantially through the addition of a mannitol bolus, as well as by the use of intracarotid artery route of infusion. In both cases, for some patients the levels after infusion approach those seen in blood, whereas the ECF levels for intravenous infusion without mannitol are typically less than 10% of the blood values

The association between dietary macronutrient intake and fibrogen growth factor 21 in a sample of White UK adults with elevated cardiometabolic risk markers

Increased levels of Fibrogen growth factor 21 (FGF21) is an emerging risk marker for cardiometabolic (CM) disease(1). Little detail is known about the impact of the human diet on FGF21 levels. The aim of this investigation was to assess potential associations between mean daily dietary macronutrient intake and FGF21 levels in a sample of 10 healthy normal-weight and overweight Caucasian adults aged 32–60 (80 % male) at increased CM risk(2). This pilot study received ethical approval from Liverpool John Moores University Research Ethics Committee (16/ELS/029) and was registered with ClinicalTrials.gov (Ref. NCT03257085). Participants were randomly allocated to one of two groups and asked to either consume 50 % energy from CHO for a duration of 8 weeks. Blood plasma samples were col- lected at baseline (BL), interim point (IP) and endpoint (EP) after a 12-hour overnight fast, immediately processed and frozen at −80°C. Thawed plasma samples were analysed via Quantikine® enzyme-linked immunosorbent assay (ELISA) (R&D Systems) for FGF21 levels. Two-way mixed ANOVA and Pearson’s partial correlation adjusted for estimated weekly moderate and vigorous activity was undertaken using IBM SPSS 24®. There were no effects for diet between groups or over time (data not shown). Significant correlations between macronutrient intakes and FGF21 levels were found for both groups at IP, but not at BL or EP. Moderate and significant positive correlations were found in the overall group for intake (g/d) for glucose (rpartial = ·699, p = ·04) and fructose (rpartial = ·686, p = ·04) and strong and significant positive correlations for non-milk extrinsic sugars (rpartial = ·742, p = ·02). Strong and significant positive correlations were also found in the LC group for glucose intake (g/d) (rpartial = ·980, p = ·02) and fructose (rpartial = ·967, p = ·03) and for protein (rpartial =·998, p=·002) after adjusting for physical activity. Mean carbohydrate intake (g/d) was 160·0 (s.d. 124·5) overall and 44·2 (s.d. 14·9) in the LC group at IP. Mean protein intake (g/d) was 113·2 (21·4) 130·0 (s.d. 15·9) overall and in the LC group at IP. Mean FGF21 levels were 179·9 pg/mL (s.d. 144·9) in the overall group and 94.4 pg/ML (s.d. 48.6) in the LC group at IP. %TE Intake (g/d) PROT FAT CHO GLU FRU NMES PROT FAT rrrrrrrrrrr −·214 ·623 ·635 −·326 −·491 ·448 ·699* ·686* ·742* −·606 −·496 ·143 ·637 ·937 ·427 −·059 ·722 ·980* ·967* ·919 ·998** −·080 Total kcal CHO NMES T LC CHO-Total carbohydrates, FAT-Total fat, FRU-Fructose, GLUC-Glucose, LC-low-carbohydrate, high-fat group, NMES-non-milk extrinsic sugars, PROT-protein, T – total, %TE – percentage total energy, *p < ·05 **p < ·005. In conclusion, low-carbohydrate diets provide the opportunity to assess responses to even small amounts of CHO, which are likely to be replaced in part by proteins. Despite low overall intakes of fructose and glucose in the LC group, strong and positive correlations with FGF21 levels were observed. The lower levels of FGF21 in the LC compared to the overall group are in line with findings that FGF21 levels are elevated with high-carbohydrate, low-protein diets with dietary fats having only minor impact(3). However, the majority of studies have still been undertaken using rodent models. The impact of dietary macronutrients on FGF21 levels as novel CMR marker in humans and the mechanism behind this relationship warrant further investigation. 1. Lakhani I, Gong M, Wong W et al. (2018) Metabolism 2018 Feb 1. pii: S0026-0495(18)30023-4. [Epub ahead of print]. 2. Jebb S, Lovegrove J, Griffin B et al. (2010) Am J Clin Nutr 92, 748–58. 3. Solon-Biet S, Cogger V, Pulpitel T et al. (2016) Cell Metab 24, 555–565

Dietary carbohydrate intake, visceral adipose tissue and associated markers of cardiometabolic risk

Risk of cardiometabolic (CM) disease is characterised by elevated visceral adipose tissue (VAT) and a number of associated biomar- kers(1). Some dietary carbohydrates (CHO) have been found to contribute to VAT accumulation(2). Little is known about the impact of following a low-carbohydrate diet versus a high-carbohydrate diet on VAT, adiponectin (ADPN), leptin (LEPT) and leptin:adipo- nectin ratio (LAR). The aim of this investigation was to assess the impact of dietary carbohydrates (CHO) on VAT and emerging CM risk markers in a sample of 10 healthy normal-weight and overweight Caucasian adults aged 32–60 (80 % male) at increased CM risk(3). This pilot study received ethical approval from Liverpool John Moores University Research Ethics Committee (16/ELS/ 029) and was registered with ClinicalTrials.gov (Ref. NCT03257085). Participants were randomly allocated to one of two groups and asked to either consume 50 % energy from CHO (high-carb (HC)) for a duration of 8 weeks. VAT was ana- lysed via bioelectrical impedance (SECA mBCA 515). Blood plasma samples were collected at baseline (BL), interim point (IP) and endpoint (EP) after a 12-hour overnight fast, immediately processed and frozen at -80°C. Thawed plasma samples were analysed via immunoassay technology (Randox Evidence InvestigatorTM Metabolic Syndrome Arrays I and II) for ADPN and LEPT levels. Statistical analysis was undertaken using IBM SPSS 24®. Parametric data was analysed via two-way mixed ANOVA; non-parametric data was analysed via Mann-Whitney U test and Friedman test. Average daily carbohydrate intake in the LC group was 44·2 g at IP and 48·9 g at EP. There were no significant differences between groups at any time point for ADPN, LEPT, LAR or VAT and no significant inter- actions for time or group*time for ADPN, LEPT or LAR. However, in the LC group VAT decreased significantly between baseline and endpoint by 15 % (p = ·015) Over the course of the intervention ADPN and LEPT decreased non- significantly (by 4 % and 70 % respectively) in the LC group, whilst increasing non-significantly in the HC group (9 % and 65 % respectively). LAR increased in the HC group throughout the study, whilst LAR in the LC group decreased albeit not significantly. VAT (litre) ADPN (ng/mL) LEPT (ng/mL) LAR BL IP EP Median Median Median M SD M SD M SD BL IP EP BL IP EP BL IP EP LC 4·1a 1·2 3·8 1·3 3·5a 1·2 8·9 8·6 8·5 3·96 1·64 1·20 0·45 0·19 0·14 HC 2·7 0·1 1·6 0·3 2·5 0·1 11·3 13·4 12·3 0·97 1·1 1·60 0·07 0·07 0·46 ADPN = adiponectin, BL = baseline, EP = endpoint, HC = high-carbohydrate, moderate fat diet, IP = interim point, LAR = leptin:adiponectin ratio, LEPT = leptin, LC = low-carbohydrate, high-fat diet, VAT = visceral adipose tissue, ap = ·015. NB: interquartile ranges not provided for median values due to missing data. Higher LAR has been found to be a marker of increased CM risk(4). In conclusion, while the significant reduction in VAT in the LC group corresponds with the reduction of LAR further evidence is required to corroborate these findings. Previous evidence for LC is supportive for improved CM health from various biomarkers(5); LAR should be considered as a useful endocrine addition for future LC studies. 1. Krasimira A, Mozaffarian D & Pischon T (2018) Clin Chem 64, 142–153. 2. Rüttgers D, Fischer K, Koch M et al. (2015) Br J Nutr 114, 1929–1940. 3. Jebb S, Lovegrove J, Griffin B et al. (2010) Am J Clin Nutr 92, 748–58. 4. López-Jaramillo P, Gómez-Arbeláez D, López-López J et al. (2014) Horm Mol Biol Clin Investig 18, 37–45. 5. Bazzano L, Hi T, Reynolds K et al. (2014) Ann Intern Med 161, 309–318

Troubling meanings of "family" for young people who have been in care: from policy to lived experience

This article seeks to trouble the concept of “family” for young people who have been in out-of-home care, by reflecting on the continuing significance (and troubles) of family relationships beyond childhood. The analysis draws on two cross-national studies in Europe: Beyond Contact, which examined policies and systems for work with families of children in care, and Against All Odds?, a qualitative longitudinal study of young adults who have been in care. Policy discourses that reify and instrumentalize the concept of family—for example, through the language of “contact,” “reunification,” and “permanence”—neglect the complex temporality of “family” for young people who have been in care, negotiated and practiced across time and in multiple (and changing) care contexts, and forming part of complex, dynamic and relational identities, and understandings of “belonging” for young adults who have been in care